EP0184754B1 - Compositions à base d'enzymes pancréatiques et procédé pour leur préparation - Google Patents

Compositions à base d'enzymes pancréatiques et procédé pour leur préparation Download PDF

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Publication number
EP0184754B1
EP0184754B1 EP85115284A EP85115284A EP0184754B1 EP 0184754 B1 EP0184754 B1 EP 0184754B1 EP 85115284 A EP85115284 A EP 85115284A EP 85115284 A EP85115284 A EP 85115284A EP 0184754 B1 EP0184754 B1 EP 0184754B1
Authority
EP
European Patent Office
Prior art keywords
pancreatic
core
pancreatic enzyme
preparations
enzyme product
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP85115284A
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German (de)
English (en)
Other versions
EP0184754A2 (fr
EP0184754A3 (en
Inventor
Werner Dr. Fülberth
Hans-Georg Freuer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoechst AG
Original Assignee
Hoechst AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
Priority to AT85115284T priority Critical patent/ATE73669T1/de
Publication of EP0184754A2 publication Critical patent/EP0184754A2/fr
Publication of EP0184754A3 publication Critical patent/EP0184754A3/de
Application granted granted Critical
Publication of EP0184754B1 publication Critical patent/EP0184754B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form

Definitions

  • pancreatic enzyme preparations that are used for the therapy of insufficient digestive performance: They should contain a sufficient amount of good quality pancreatic enzyme . This requires a high enzyme activity. However, the therapeutic value of these preparations is only ensured if their galenical processing is adapted to the high enzyme activity. An important prerequisite for an effective substitution therapy is, among other things, the rapid and complete release of the enzymes in the digestive tract. The preparations should release the digestive enzymes immediately under the pH conditions of the duodenum.
  • pancreatic enzyme preparations are the initial activity of the enzymes, gastric juice resistance for protection against the inactivating influence of gastric acid, disintegration time and release rate of the enzymes, the lipase release being of particular importance for an effective pancreatic enzyme substitution.
  • Another requirement relates to the stability of the ferment during the entire manufacturing process and during storage.
  • pancreatic enzyme preparations especially if they contain a high percentage of organic ferment dry preparations, substance-specific and procedural difficulties that conflict with the requirements for this preparation group have to be overcome. It has therefore already been described that, in the case of a large number of commercial preparations, the enzymes required are not in sufficient quantities, but above all are not suitable Time are released (H. Möller, Pharm. Ztg. 125 , 2254-2258 (1980)). Production or storage-related enzyme losses could also be determined in the comparative test. It is also striking that in many preparations, especially those with a high proportion of ferment, the requirements of the pharmacopoeia for gastric juice-soluble or gastric juice-resistant coated tablets are not met.
  • pancreatin preparations with an average dose of 300 - 400 mg can still be formulated according to the biopharmaceutical requirements, the problems become obvious when it comes to bringing pancreatin quantities of 700 - 800 mg into a patient-friendly pharmaceutical form, especially with the high-dose preparations the release rate is very slow compared to the lower doses. Therefore, there are literature references only for the production of compressed, rapidly disintegrating pancreatin preparations with an average dose of 300-400 mg (cf. e.g. German Offenlegungsschrift 2,035,739 or corresponding Derwent Ret. 08513 T (1972))
  • pancreatic enzyme preparations Since the rate of release of the enzymes and the disintegration characteristics of pancreatic enzyme preparations are closely related, the use of a highly active tablet disintegrant is essential for the high-dose preparations with a pancreatin content of 700 - 800 mg.
  • the use of tablet disintegrants in pancreatic enzyme preparations has already been described (cf. E. Graf et al. Pharm. Ind. 44 , 317-321 (1982)).
  • pancreatin nucleus which has a high proportion of a rapid enzyme release to contain highly active tablet disintegrants with a protective coating based on organic solvents.
  • the protective coatings are required against the inactivating influence of the gastric juice and to reduce environmental influences that reduce stability. They also prevent unwanted contact with the pancreatic enzyme during the swallowing process.
  • they are applied as varnishes based on organic solvents. Chloroform, acetone and isopropanol have proven to be particularly gentle solvents. Water, especially in combination with heat, should be avoided because of its enzyme-inactivating effect (cf. E. Graf et al., Pharm. Ind.
  • the problem now is to prevent solvents from penetrating into the film-coated tablet cores during the coating process. Last but not least, this is necessary because small amounts of residual solvent remaining in the core create a swelling pressure even after storage, especially at higher temperatures, by acting on the tablet disintegrant. This leads to the formation of hairline cracks and a change in the pore structure in the protective film.
  • pancreatin An additional stability-reducing factor results from the interaction between pancreatin and the film cover.
  • the lipase contained in pancreatin can cause it to deteriorate during storage an ester cleavage and thus a chemical change in the film, which affects the resistance to gastric juice.
  • the invention therefore relates to a process for the production of a pancreatic enzyme preparation in pressed form, which is characterized in that an aqueous-based insulating layer consisting of syrup containing sugar and optionally gelatin, arabic gum, starch, polyvinylpyrrolidone, highly disperse silicon dioxide is added to the active substance-containing core.
  • an aqueous-based insulating layer consisting of syrup containing sugar and optionally gelatin, arabic gum, starch, polyvinylpyrrolidone, highly disperse silicon dioxide is added to the active substance-containing core.
  • the insulating layer is applied in two phases in the method according to the invention.
  • the cores are mixed with a, preferably warmed, cover syrup until they start to stick.
  • cover powder is added until the seeds roll freely again.
  • the covered cores must be dried thoroughly. This can be done with an air blower. Two to five of these cover layers are generally sufficient to provide effective protection against penetrating solvents and to isolate the core from the final film layer.
  • the final film layer is a lacquer layer based on organic solvents. It can be gastric juice soluble or gastro-resistant.
  • both low-dose pancreatic enzyme preparations that is, those with an active ingredient content of up to approximately 500 mg, are obtained, as well as high-dose ones, which contain approximately 500 to 1000 mg of pancreatic enzymes.
  • pancreatin cores with a high proportion of an active tablet disintegrant are effectively protected against the penetration of solvents during the final coating process by cover layers on an aqueous basis without changing their enzyme release characteristics.
  • the cores are sufficiently mechanically stabilized by the cover layer, so that no rolling wear can be determined during the painting process.
  • the preparations according to the invention contain, for example, 100 to 1000 mg, preferably 500 to 1000 mg, in particular 700 to 800 mg of pancreatin per dosage unit.
  • they can furthermore contain active substances customary for pancreatic enzyme preparations such as dimethylpolysiloxane, bovine bile, dehydrocholic acid, hemicellulase, bromelain, vegetable lipase concentrates and 2-ethoxy-6,9-diamino-acridine-DL-lactate (or other physiologically tolerable salts thereof).
  • disintegration-accelerating tablet disintegrants in a concentration of 1 to 20 wt.
  • sodium chloride can be added to support the decay accelerating effect of the aforementioned disintegration aids.
  • auxiliaries and carriers include, for example, microcrystalline cellulose, polyethylene glycol, powdered fiber cellulose, highly disperse silicon dioxide, dicalcium phosphate dihydrate, aluminum hydroxide gel.
  • So-called insulating or cover layers are applied to isolate the core containing pancreatin.
  • cover layers applied in 2 phases consist of a cover syrup, for example aqueous sugar syrup, 50 to 65%, with small additives such as gelatin, arabic gum, starch, polyvinylpyrrolidone, highly disperse silicon dioxide, sodium carboxymethyl cellulose, sodium alginate, polyvinyl alcohol, calcium carbonate. They still consist of a cover powder .
  • Mixtures containing talc, calcium carbonate, powdered sugar, highly disperse silicon dioxide, titanium dioxide, arabic gum are preferably used for this.
  • the final film layer can be both gastric juice soluble and gastric juice resistant.
  • the gastric juice-soluble paints contain, for example, the following film formers: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, copolymer with a cationic character based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters (Eudragit (R) -E).
  • the gastric juice-resistant protective covers consist, for example, of cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, copolymers with an anionic character based on methacrylic acid and methacrylic acid esters (Eudragit (R) L or S).
  • Auxiliaries such as titanium dioxide, iron oxide pigments, talc and plasticizers such as polyethylene glycols, castor oil, triethyl citrate, phthalic acid esters, glycerine fatty acid esters are also suitable for both coating systems.
  • Conventional organic solvents optionally in a mixture with water, are used in both coating systems.
  • pancreatic enzyme preparation The release of lipase from a pancreatic enzyme preparation is a test parameter for the pharmaceutical availability of pancreatin. It was determined as described below for high-dose preparations according to the invention and known preparations.
  • the lipase release was tested according to Method II described by H. Möller (Pharm. Ztg. 125 , 2254-2258 (1980)): Paddle equipment according to USP XX Test liquid: NaCl 2.0 g NaH2PO4 ⁇ H2O 9.2 g Aqua dest. ad 1000 ml
  • test liquid was adjusted to pH 3 or pH 6 with 6N HCl or NaOH conc. set.
  • the enzyme lipase which is important for the digestive process, is not released in sufficient concentration and, above all, not at the appropriate time.
  • the preparations according to the invention give in the period essential for the digestive process, i.e. The lead enzyme lipase is completely or almost completely free within 2 hours after passage through the stomach.
  • the cores are provided in a coating pan with 3 cover layers (insulating layers) in the following way: First the cores moved in the boiler are mixed with the heated cover syrup 2. until they start to stick.
  • the dried kernels are coated in the usual way with an enteric protective lacquer and then coated.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
  • Saccharide Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Steroid Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Claims (7)

  1. Procédé pour la préparation d'une composition d'enzymes pancréatiques sous forme comprimée, caractérisé en ce que l'on applique sur le noyau contenant la substance active une couche isolante à base aqueuse qui est formée à partir d'un sirop de pré-enrobage contenant un sucre et éventuellement de la gélatine, de la gomme arabique, de l'amidon, de la polyvinylpyrrolidone, de la silice fortement dispersée, de la carboxyméthylcellulose sodique, de l'alginate de sodium, du poly(alcool vinylique) ou du carbonate de calcium, et d'une poudre de pré-enrobage contenant un mélange choisi parmi le talc, le carbonate de calcium, le sucre en poudre, la silice fortement dispersée, le dioxyde de titane et la gomme arabique, et l'on munit ensuite ce noyau d'une couche de laque à base de solvants organiques.
  2. Procédé selon la revendication 1, caractérisé en ce que l'on utilise, en tant que sirop de pré-enrobage, un sirop de sucre qui peut contenir en outre de la gélatine et de l'amidon.
  3. Procédé selon la revendication 1, caractérisé en ce que l'on utilise, en tant que poudre de pré-enrobage, un mélange de talc et de carbonate de calcium.
  4. Procédé selon la revendication 1, caractérisé en ce que l'on utilise des noyaux contenant de 500 à 1 000 mg d'enzymes pancréatiques et de 1 à 20 % en poids, par rapport aux enzymes pancréatiques, d'un désintégrant usuel.
  5. Procédé selon la revendication 1, caractérisé en ce que l'on prépare des compositions ayant une teneur en enzymes pancréatiques allant de 700 à 800 mg et contenant de 1 à 20 % en poids, par rapport à la teneur en enzymes pancréatiques, d'un désintégrant usuel.
  6. Procédé selon la revendication 1, caractérisé en ce que l'on prépare une composition qui contient dans le noyau encore d'autres substances actives usuelles pour des composisitions d'enzymes pancréatiques.
EP85115284A 1984-12-12 1985-12-02 Compositions à base d'enzymes pancréatiques et procédé pour leur préparation Expired - Lifetime EP0184754B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT85115284T ATE73669T1 (de) 1984-12-12 1985-12-02 Pankreasenzympraeparate und verfahren zu deren herstellung.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3445301 1984-12-12
DE19843445301 DE3445301A1 (de) 1984-12-12 1984-12-12 Pankreasenzympraeparate und verfahren zu deren herstellung

Publications (3)

Publication Number Publication Date
EP0184754A2 EP0184754A2 (fr) 1986-06-18
EP0184754A3 EP0184754A3 (en) 1987-09-30
EP0184754B1 true EP0184754B1 (fr) 1992-03-18

Family

ID=6252579

Family Applications (1)

Application Number Title Priority Date Filing Date
EP85115284A Expired - Lifetime EP0184754B1 (fr) 1984-12-12 1985-12-02 Compositions à base d'enzymes pancréatiques et procédé pour leur préparation

Country Status (14)

Country Link
US (1) US4859471A (fr)
EP (1) EP0184754B1 (fr)
JP (1) JPS61145124A (fr)
KR (1) KR930001277B1 (fr)
AT (1) ATE73669T1 (fr)
AU (1) AU592325B2 (fr)
CA (1) CA1247526A (fr)
DE (2) DE3445301A1 (fr)
DK (1) DK572985A (fr)
ES (1) ES8705759A1 (fr)
GR (1) GR852955B (fr)
IE (1) IE58621B1 (fr)
PT (1) PT81649B (fr)
ZA (1) ZA859482B (fr)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988001512A1 (fr) * 1986-08-28 1988-03-10 Thomas Ko Sai Ying Promoteur de croissance animale
DE3642853A1 (de) * 1986-12-16 1988-06-23 Ulrich Von Dr Ing Pidoll Arzneimittel
US5026560A (en) * 1987-01-29 1991-06-25 Takeda Chemical Industries, Ltd. Spherical granules having core and their production
JP3025528B2 (ja) * 1989-11-24 2000-03-27 ビオヘミー・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング パンクレアチン製剤
US5175003A (en) * 1990-04-06 1992-12-29 Biosytes Usa, Inc. Dual mechanism controlled release system for drug dosage forms
US5302400A (en) * 1992-06-22 1994-04-12 Digestive Care Inc. Preparation of gastric acid-resistant microspheres containing digestive enzymes and buffered-bile acids
US5750104A (en) * 1996-05-29 1998-05-12 Digestive Care Inc. High buffer-containing enteric coating digestive enzyme bile acid compositions and method of treating digestive disorders therewith
IT1319655B1 (it) 2000-11-15 2003-10-23 Eurand Int Microsfere di enzimi pancreatici con elevata stabilita' e relativometodo di preparazione.
US9011843B2 (en) * 2006-12-14 2015-04-21 Master Supplements, Inc. Formulations including monovalent alginate to enhance effectiveness of administered digestive enzymes
SG186648A1 (en) 2007-02-20 2013-01-30 Aptalis Pharma Ltd Stable digestive enzyme compositions
US10087493B2 (en) 2008-03-07 2018-10-02 Aptalis Pharma Canada Ulc Method for detecting infectious parvovirus in pharmaceutical preparations
EP2484383B1 (fr) * 2009-09-30 2021-04-28 Kabushiki Kaisha Sangi Procédé permettant d'améliorer la solubilité aqueuse de substances médiocrement solubles
UA111726C2 (uk) 2010-10-01 2016-06-10 Апталіс Фарма Лімітед Препарат панкреліпази низької сили з кишковорозчинним покриттям
AU2012293325B2 (en) 2011-08-08 2015-05-07 Allergan Pharmaceuticals International Limited Method for dissolution testing of solid compositions containing digestive enzymes
JP5909796B2 (ja) 2012-03-02 2016-04-27 株式会社サンギ 難溶性物質の水溶解性改善方法
US10993996B2 (en) 2013-08-09 2021-05-04 Allergan Pharmaceuticals International Limited Digestive enzyme composition suitable for enteral administration
WO2015193730A1 (fr) 2014-06-19 2015-12-23 Aptalis Pharma Ltd. Procédés d'élimination de contaminants viraux dans des extraits pancréatiques

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE163891C (fr) *
CH163891A (de) * 1931-11-13 1933-09-15 Kalle & Co Ag Verfahren zur Herstellung von haltbaren Pankreasamylase-Trockenpräparaten.
DE1063758B (de) * 1955-03-23 1959-08-20 Upjohn Co Im Darmtrakt loesliche Arzneimittelschutzumhuellungen
FR1537651A (fr) * 1961-10-24 1968-09-07 Denver Chemical Mfg Company Procédé de préparation de composition solide à enduit entérique
GB986254A (en) * 1962-12-11 1965-03-17 Upjohn Co Coated tablets
DE2035739A1 (en) * 1970-07-18 1972-01-27 Röhm FmbH, 6100 Darmstadt Oral enzyme prepsn - consisting of granulate with gastric juices-resistant coating in tablet or capsule form

Also Published As

Publication number Publication date
IE853130L (en) 1986-06-12
DE3445301A1 (de) 1986-06-12
PT81649B (pt) 1988-02-17
GR852955B (fr) 1986-04-01
CA1247526A (fr) 1988-12-28
KR930001277B1 (ko) 1993-02-25
AU592325B2 (en) 1990-01-11
ES8705759A1 (es) 1987-05-16
JPS61145124A (ja) 1986-07-02
ZA859482B (en) 1986-08-27
EP0184754A2 (fr) 1986-06-18
KR860004636A (ko) 1986-07-11
AU5117985A (en) 1986-06-19
DK572985A (da) 1986-06-13
PT81649A (de) 1986-01-01
DE3585672D1 (de) 1992-04-23
EP0184754A3 (en) 1987-09-30
IE58621B1 (en) 1993-10-20
ES549757A0 (es) 1987-05-16
DK572985D0 (da) 1985-12-11
US4859471A (en) 1989-08-22
ATE73669T1 (de) 1992-04-15

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